Imbalance of Mitochondria Dynamics Contributes to Mitochondrial Dysfunction and Metabolic Deterioration in Skeletal Muscle

Mitochondria are highly dynamic organelles, undergoing frequent fusion and fission, which are regulated by the machinery involving Mfn1, Mfn2 and OPA1 for fusion, and Drp1 and Fis1 for fission. The balance of fusion and fission is critical in the maintenance of mitochondrial morphology and function. Mitochondrial dysfunction resulted from reduced mitochondrial biogenesis is known to underlie obesity-induced metabolic disturbances. However, the role of mitochondrial dynamics in the pathogenesis of obesity-induced metabolic disorder remains unclear. Here, we hypothesized that obesity alters mitochondrial dynamics, contributing to mitochondrial dysfunction and metabolic disturbances. First, we observed smaller and shorter mitochondria in the skeletal muscle of obese mice, and this was associated with increased mitochondria-associated Fis1 protein in gastrocnemius skeletal muscle of obese mice. These results suggest that mitochondrial dynamics is shifted toward fission upon obesity. To investigate which factors in the obese state alter mitochondrial dynamics, differentiated C2C12 myotubes were incubated with excess fatty acid or glucose. While unsaturated fatty acids and glucose did not alter mitochondrial morphology, saturated fatty acids including palmitic acid (PA) and myristric acid induced mitochondrial fragmentation in a time dependent manner. PA-induced mitochondrial fragmentation was accompanied by impairments of mitochondrial polarization and ATP generation. Interestingly, docosahexaenoic acid (DHA) rescued mitochondrial fragmentation and impairments of mitochondrial polarization and ATP generation induced by PA. Taken together, our findings demonstrated that mitochondrial dynamics is shifted toward fission in the skeletal muscle under the obese condition. The alteration of mitochondrial dynamics resulted from excess PA leads to mitochondrial dysfunction in muscle cells.